Nano-delivery systems are promising vehicles in drug delivery because they improve solubility of hydrophobic drugs, increase local concentration, provide longer clearance time, increase probability of interactions (e.g. when activation of a receptor is critical), and generally have low toxicity. It has been observed that to avoid clearance by the reticuloendothelial system (RES), the addition of polyethylene glycol (PEG) on the surface of NPs is required (Storm et al., “Surface modification of nanoparticles to oppose uptake by the mononuclear phagocyte system,” Adv. Drug Delivery Rev. 17:31-48 (1995)). As a consequence of surface PEG molecules, higher maximum tolerated doses (MTD) of nanoparticles (NPs) are realized (Alexis et al., “Nanoparticle technologies for cancer therapy,” Handb. Exp. Pharmacol. 197:55-86 (2010)). However, certain nano-delivery systems, such as liposomes and dendritic polymers, suffer from deficiencies, such as failure to regulate half-life of a drug once released in vivo.
Osteoarthritis is the most common form of arthritis affecting as many as 29 million people in the United States alone. One in every two people will likely be affected by osteoarthritis. The pathogenesis of osteoarthritis involves low grade inflammation, destruction of articular cartilage and reactive overgrowth of bone in the affected joints. At present therapy is, for the most part palliative, including use of nonsteroidal anti-inflammatory drugs (e.g. ibuprofen), narcotic analgesics, exercise, acupuncture, and injections of anti-inflammatory agents (e.g. glucocorticoids) or other substances (hyaluronic acid) into the joint. Ultimately many patients will undergo replacement of the affected joints.
A very large portion of the heath care budget in the United States relates to the treatment of osteoarthritis (total (direct and indirect) annual costs of osteoarthritis per patient=$5700 FY2000, www.cdc.gov/arthritis/basics/osteoarthritis.htm). Thus, costs, including loss of work, cost of hospitalization for joint replacement and repair surgery and other types of therapy are high and consume a large percentage of the US national health budget. The populations of other developed and developing countries suffer at a similar rate. Moreover, due to increasing obesity and overweight of the population the incidence of knee osteoarthritis and the frequency of total knee replacement is expected to increase dramatically in the near future. At present, short of total joint replacement, there are few long-term effective therapies available. Moreover, although currently available injectable agents (corticosteroids, hyaluronate) provide symptomatic relief none of these agents are restorative. Therefore, improved and more effective treatments of osteoarthritis are required.
The present invention is directed to overcoming these and other deficiencies in the art.